Leptin Receptor Expression in GABAergic Cells is Not Sufficient to Normalize Metabolism and Reproduction in Mice

Author(s)

Quaresma, Paula G. F. ^[1] ; Wasinski, Frederick ^[1] ; Mansano, Naira S. ^[2] ; Furigo, Isadora C. ^[1] ; Teixeira, Pryscila D. S. ^[1] ; Gusmao, Daniela O. ^[1] ; Frazao, Renata ^[2] ; Donato Jr, Jose

Affiliation

^[1] Univ Sao Paulo, Inst Ciencias Biomed, Dept Fisiol & Biofis, BR-05508000 Sao Paulo, SP - Brazil

^[2] Univ Sao Paulo, Inst Ciencias Biomed, Dept Anat, BR-05508900 Sao Paulo, SP - Brazil

• Document type: Journal article
• Source: Endocrinology; v. 162, n. 11 NOV 2021.
• Web of Science Citations: 1

Abstract

Previous studies indicate that leptin receptor (LepR) expression in GABAergic neurons is necessary for the biological effects of leptin. However, it is not clear whether LepR expression only in GABAergic neurons is sufficient to prevent the metabolic and neuroendocrine imbalances caused by LepR deficiency. In the present study, we produced mice that express the LepR exclusively in GABAergic cells (LepR(VGAT) mice) and compared them with wild-type (LepR(+/+)) and LepR-deficient (LepR(Null/Null)) mice. Although LepR(VGAT) mice showed a pronounced reduction in body weight and fat mass, as compared with LepR(Null/Null) mice, male and female LepR(VGAT) mice exhibited an obese phenotype relative to LepR+ 4 mice. Food intake was normalized in LepR(VGAT) mice ; however, LepR(VGAT) mice still exhibited lower energy expenditure in both sexes and reduced ambulatory activity in the females, compared with LepR(+/+) mice. The acute anorexigenic effect of leptin and hedonic feeding were normalized in LepR(VGAT) mice despite the hyperleptinemia they present. Although LepR(VGAT) mice showed improved glucose homeostasis compared with LepR(Null/Null) mice, both male and female LepR(VGAT) mice exhibited insulin resistance. In contrast, LepR expression only in GABAergic cells was sufficient to normalize the density of agouti-related peptide (AgRP) and alpha-MSH immunoreactive fibers in the paraventricular nucleus of the hypothalamus. However, LepR(VGAT) mice exhibited reproductive dysfunctions, including subfertility in males and alterations in the estrous cycle of females.Taken together, our findings indicate that LepR expression in GABAergic cells, although critical to the physiology of leptin, is insufficient to normalize several metabolic aspects and the reproductive function in mice. (AU)

• FAPESP's process: 21/03316-5 - Evaluation of the importance of GABAergic and dopaminergic transmission in neurons that express the growth hormone-releasing hormone to the control of GH secretion
• Grantee: Daniela de Oliveira Gusmão
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 16/09679-4 - Central effects of growth hormone on energetic metabolism and glicemic control
• Grantee: Isadora Clivatti Furigo
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 19/21707-1 - Food deprivation effects in kisspeptin neurons excitability
• Grantee: Renata Frazão
• Support Opportunities: Regular Research Grants
• FAPESP's process: 17/25281-3 - Effects of growth hormone on POMC, cholinergic and hypothalamic paraventricular nucleus neurons: implications for energy and glycemic metabolism control
• Grantee: Paula Gabriele Fernandes Quaresma Bergonsi
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 20/01318-8 - Central nervous system as a target of growth hormone for the regulation of multiple biological functions
• Grantee: Jose Donato Junior
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 17/22189-9 - Does the factors that change food intake modulate the activity of Kiss1 neurons?
• Grantee: Naira da Silva Mansano
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 16/20897-3 - Role of orexin neurons as mediators of the central effects induced by growth hormone
• Grantee: Frederick Wasinski
• Support Opportunities: Scholarships in Brazil - Post-Doctoral